Cannabinoid receptor 2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing

Abstract

Kidney is one of the most important organs in maintaining the normal life activities. With the high abundance of mitochondria, renal tubular cell plays the vital role in functioning in the reabsorption and secretion of kidney. Reports have shown that mitochondrial dysfunction is of great importance to renal tubular cell senescence and subsequent kidney ageing. However, the underlying mechanisms are not elucidated. Cannabinoid receptor 2 is one of the two receptors responsible for the activation of endocannabinoid system. CB2 is primarily upregulated in renal tubular cells in chronic kidney diseases and mediates fibrogenesis. However, the role of CB2 in tubular mitochondrial dysfunction and kidney ageing has not been clarified. In this study, we found that CB2 was upregulated in kidneys in 24‐month‐old mice and d‐galactose (d‐gal)‐induced accelerated ageing mice, accompanied by the decrease in mitochondrial mass. Furthermore, gene deletion of CB2 in d‐gal‐treated mice could greatly inhibit the activation of β‐catenin signalling and restore the mitochondrial integrity and Adenosine triphosphate (ATP) production. In CB2 knockout mice, renal tubular cell senescence and kidney fibrosis were also significantly inhibited. CB2 overexpression or activation by the agonist AM1241 could sufficiently induce the decrease in PGC‐1α and a variety of mitochondria‐related proteins and trigger cellular senescence in cultured human renal proximal tubular cells. CB2‐activated mitochondrial dysfunction and cellular senescence could be blocked by ICG‐001, a blocker for β‐catenin signalling. These results show CB2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing. The intrinsic mechanism may be related to its activation in β‐catenin signalling.

CXC Chemokine Receptor 2 Accelerates Tubular Cell Senescence and Renal Fibrosis via β-Catenin-Induced Mitochondrial Dysfunction

“…Our previous study found that β-catenin plays a central role in mitochondrial dysfunction and renal tubular senescence ( Luo et al, 2018 ; Miao et al, 2019 ). To further study the downstream signals of CXCR2, we pretreated HKC-8 cells with ICG-001 ( Yahong Liu et al, 2020 ; Zhou et al, 2021 ), an inhibitor of β-catenin. HKC-8 cells were pretreated with ICG-001, and then transfected with CXCR2 expression plasmid.…”

“…Mitochondrial dysfunction not only leads to energy absence, but also results in the production of ROS, contributing to DNA damage and cellular senescence ( Di Micco et al, 2021 ). Our previous study showed that the activation of β-catenin was highly involved in mitochondrial dysfunction and cellular senescence, suggesting the close relationship between β-catenin and mitochondrial dysfunction ( Miao et al, 2021 ; Zhou et al, 2021 ). One of the underlying mechanisms lies in the modulation of β-catenin on PGC-1α, a master controller for mitochondrial biogenesis.…”

“…However, the upstream inducer of β-catenin in tubular cell senescence still needs to be clarified. Our recent reports showed that β-catenin mediates the effects of G protein-coupled receptors (GPCR) ( Miao et al, 2021 ; Zhou et al, 2021 ). However, the authentic role of GPCR in renal tubular cell senescence has not been elucidated, and its relationship with β-catenin is still in mystery.…”

Palmitoylethanolamide and Related ALIAmides for Small Animal Health: State of the Art

“…Although studies in small animals are still scarce, there is growing evidence that endocannabinoid-like ALIAmides play key roles in the health of different body organs, such as the gastrointestinal tract [ 113 , 114 ] and the nervous system [ 32 , 34 , 37 ], as well as the upper and lower urinary tract [ 115 , 116 , 117 , 118 ] and the musculoskeletal system [ 97 , 119 , 120 ]. In addition, the deep involvement of ALIAmides in obesity-induced metainflammation is becoming increasingly evident [ 69 , 113 , 121 , 122 , 123 ].…”

Blood Levels of Endocannabinoids, Oxylipins, and Metabolites Are Altered in Hemodialysis Patients

“…These changes might be related to large differences in the systemic use of amino acids and intermediary metabolism. Recently, the upregulation of the CB2 receptor was found to play a primary role in the mitochondrial dysfunction of renal tubular cells [ 62 ]. Thus, understanding the full extent of differences in eCBs and OxLs in the present study helps identify the relationship between dietary PUFAs and these bioactive lipids in the HDPs.…”